Villous adenoma of the urinary tract: a lesion frequently associated with malignancy

Villous adenomas arising in the urinary tract are rare. We identified 18 cases of villous adenomas of the bladder, urachus, and prostatic urethra. Patients ranged in age from 53 to 93 years with an average age of 69.6 years and a male preponderance of 67%. In six cases (33%), the lesion was pure villous adenoma. In three cases (17%), there was villous adenoma with in situ adenocarcinoma. In six cases (33%) there was villous adenoma with in situ and infiltrating adenocarcinoma. One case (6%) had villous adenomas with in situ (noninvasive) papillary urothelial carcinoma. One case (6%) had villous adenomas with in situ adenocarcinoma and in situ papillary (noninvasive) and infiltrating urothelial carcinoma. The remaining case (6%) had villous adenoma with in situ and infiltrating adenocarcinoma and in situ (noninvasive) papillary and infiltrating urothelial carcinoma. Clinical outcome was available in eight of the cases, with a mean follow-up of 4.6 years. No evidence of recurrence was found in two patients with pure villous adenoma or in two patients with villous adenoma and only in situ adenocarcinoma, all of whom were treated by nonradical excision. However, two of three cases with infiltrating cancer developed distant metastases despite radical surgery; the remaining patient was disease-free 11 years after transurethral resection. The case with villous adenoma and in situ urothelial carcinoma progressed to sarcomatoid urothelial carcinoma following partial cystectomy. Eight of 10 villous adenomas cases studied expressed the epitope for mAbDas1, found on colonic epithelium and primary adenocarcinomas of the bladder and urachus but not on normal or neoplastic urothelium. This study expands the spectrum of histologic features accompanying villous adenomas of the urinary tract. Coexisting infiltrating adenocarcinoma is often present, necessitating thorough sampling of any lesion diagnosed by biopsy as villous adenoma. Pure villous adenoma and those well-sampled lesions also containing in situ adenocarcinoma portend a favorable prognosis, even without radical treatment. Coexisting in situ or infiltrating carcinoma suggests a more aggressive course. Histologically, immunohistochemically, and prognostically, these lesions appear analogous to their counterparts in the intestine.     

Nephrogenic adenoma of the urinary tract: a review

Nephrogenic adenoma (NA) is an uncommon and intriguing lesion in the urinary tract. The pathogenesis of NA is not entirely clear. NA was considered to be a metaplastic process of the urothelium in response to chronic irritation of the urinary tract. However, recent evidence has shown that NA is not a metaplastic lesion but rather a proliferation of exfoliated and implanted renal epithelial cells in the urinary tract. Histologically, NAs exhibit, singly or in combination, tubules, small papillae, and microcystic structures lined by cells with little cytological atypia and focal hobnail changes. Solid formations and compressed spindled cells within a fibromyxoid background are rarely observed. Differential diagnosis includes, but is not limited to, malignant neoplasms occurring at the same sites, in particular urothelial carcinoma with deceptively bland morphology (with small tubules, microcystic and nested variants), prostatic adenocarcinoma, and clear cell adenocarcinoma. Immunohistochemical studies with antibodies targeting members of the paired box gene family (PAX2 and/or PAX8) in NAs may be helpful in the differential diagnosis of urothelial lesions and prostatic adenocarcinoma. NAs are most likely to be confused with clear cell adenocarcinoma, especially in small biopsy specimens. This is confounded by both lesions being frequently positive for PAX2, PAX8, and CK7 and not infrequently positive for p504S (α-methylacyl-CoA-racemase, AMACR) by immunohistochemistry. Recognition of its characteristic morphological patterns and awareness of its unusual architectural and cytological features are important in making the diagnosis of NA and distinguishing this lesion from its mimickers.     

Villous adenoma of the urinary tract; a clinicopathological study北大核心CSCD

Objective: To explore the clinicopathological features, immunophenotype, differential diagnosis, pathogenesis and prognosis of villous adenoma with poorly differentiated adenocarcinoma of the urinary tract. Methods: Clinical and pathologic findings of 3 cases of villous adenoma with poorly differentiated adenocarcinoma of the urinary tract were analyzed by gross examination, microscopic investigation and immunohistochemical staining. The related literatures were reviewed. Results: All of the three cases were middle-aged or elderly patients. Three cases all presented with hematuria and mucusuria. Endoscopic examination identified that case 1 had a polyp with broad attachment in the dome of bladder, case 2 had a solid mass in the ureter, and case 3 had a exophytic fungating tumor in the renal pelvis. Microscopically, case 1 revealed a papillary lesion with finger-like processes lined by pseudostratified columnar epithelium with abundant goblet cells. The cells demonstrated moderate degree dysplasia. In case 2 and case 3, both villous adenomas and poorly differentiated adenocarcinoma were observed, the adenoma cells arranged in a cribriform pattern, and the tumor cells showed severe atypia, mitotic activity, and transition with invasive poorly differentiated adenocarcinoma. Immunohistochemically, the tumor cells in three cases were positive for CK20,CEA,EMA and MUC-1; none of them expressed cdx-2 and PSA; In case 2 and 3, the same immunophenotype of villous adenomas and their associated adenocarcinomas was observed, but the number of the positive cells of p53 and Ki-67 staining were significantly increased in the area of adenocarcinomas than in that of the villous adenomas. Conclusions: Villous adenoma of the urinary tract is rare. It can occur in the urinary bladder, urachus, renal pelvis, ureter and urethra. These lesions may have malignant potential and frequently coexist with other malignant tumors. So, villous adenoma of the urinary tract should be removed completely and sampled thoroughly to avoid missing a more aggressive component.     

Clear cell adenocarcinoma and nephrogenic adenoma of the urethra and urinary bladder: A histopathologic and immunohistochemical comparison

Because of histological similarities between nephrogenic adenomas and clear cell adenocarcinomas of the urinary tract, there is the potential for diagnostic confusion between these two entities. The histopathologic features of 13 nephrogenic adenomas and five clear cell adenocarcinomas of the urethra and urinary bladder are compared in this report, and detailed immunohistochemical staining profiles are provided for these tumors. Only 2 of the 13 nephrogenic adenomas contained clear cells, and these constituted less than 10% of the lesions. In contrast, four of the five clear cell adenocarcinomas contained prominent areas with clear cells. Nephrogenic adenomas generally showed only mild cytologic atypia, whereas four of the five clear cell adenocarcinomas showed severe atypia. A single mitotic figure was identified in only two of the nephrogenic adenomas, whereas the mitotic rate in the clear cell adenocarcinomas ranged from 2 to 14 per 10 high-power fields. None of the nephrogenic adenomas showed evidence of necrosis, but focal necrosis was noted in four of the five clear cell adenocarcinomas. In general, the nephrogenic adenomas and clear cell adenocarcinomas showed negative to weak staining with CK903 but strong staining with AE1, AE3, and Cam 5.2. Variable staining was observed with Brst-3 and antibodies to S-100, CEA (monoclonal and polyclonal), LeuM-1, and CA19.9. Nephrogenic adenomas and dear cell adenocarcinomas were all negative for prostate-specific acid phosphatase (PSAP), prostate-specific antigen (PSA), and estrogen and progesterone receptors (except for two nephrogenic adenomas, which showed only focal weak staining for estrogen receptor). Neither bcl-2 nor c-erbB-2 staining was able to discriminate between the tumors. However, strong staining for p53 was noted in each clear cell adenocarcinoma and in none of the nephrogenic adenomas. MIB-1 positivity in nephrogenic adenomas ranged from 0 to 13 (average of 5.5) per 200 cells, whereas the positive range for clear cell adenocarcinomas was 33 to 70 (average of 47) per 200 cells. In summary, histopathologic features that favor clear cell adenocarcinoma over nephrogenic adenoma include a predominance of clear cells, severe cytological atypia, high mitotic rate, necrosis, high MIB-1 positivity, and strong staining for p53.     

Urinary bladder adenocarcinoma arising in a spina bifida patient

Urinary bladder adenocarcinomas are rare malignancies accounting for approximately 2.5% of all urothelial neoplasms. Intestinal metaplasia of the urothelium indicates the presence of intestinal-type goblet cells and was generally observed to coexist with or to precede the diagnosis of bladder adenocarcinomas. Controversy continues of whether intestinal metaplasia is an acquired precancerous lesion, secondary to different insults to the urothelium, or a concomitant lesion in glandular carcinogenesis. Patients with neurogenic bladders are particularly at risk for developing bladder cancer, mostly squamous cell carcinoma and rarely adenocarcinoma. In these patients, chronic irritation of the urothelium as well as long-term indwelling urinary catheters were the most significant risk factors. Spina bifida is a congenital developmental abnormality that may result in neurogenic bladder. There is only one previously reported case of urothelial carcinoma with associated squamous metaplasia of the bladder occurring in a spina bifida patient. We report the first case of bladder adenocarcinoma associated with intestinal metaplasia occurring in a spina bifida occulta patient. The patient had a complicated clinical course and suffered recurrent urinary tract infections, renal calculi, and urinary incontinence and was managed with intermittent as well as indwelling catheterization.     

Villous adenoma of urinary tract: a common tumor in an uncommon location

The presence of colonic-type epithelium in the urinary tract is not an uncommon occurrence, but tumors derived from it are rare. Tumors arising from colonic-type epithelium, including villous adenoma and adenocarcinoma, have been reported in the renal pelvis, ureter, urinary bladder, and urethra. Villous adenomas of the urinary tract are rare, being most common in the urinary bladder, followed by the urethra. Morphologic features of these tumors are similar to those of the colonic adenomas. The largest published series of villous adenomas of the urinary tract was a study of 23 patients. This study is reviewed and other reports on villous adenomas of the urinary tract are discussed.     

High-grade carcinomas involving the renal sinus: report of a case and review of the differential diagnosis and immunohistochemical expression

We report the case of a high-grade carcinoma involving the kidney in a young male with renal vein thrombosis and review the differential diagnosis and immunohistochemical workup. High-grade neoplasms involving the renal sinus include collecting duct carcinomas (CDCs), renal medullary carcinomas (RMCs), invasive high-grade urothelial carcinoma (UC) of the upper urinary tract, clear cell renal cell carcinoma, and type 2 papillary renal cell carcinoma. Distinguishing UC from CDC and RMC is problematic in small biopsy samples. The diagnosis of CDC (a rare, aggressive subtype of renal cell carcinoma) is challenging and requires the exclusion of UC. Renal medullary carcinoma is characterized by an appropriate clinical setting and consistent loss of nuclear expression of integrase interactor 1 (INI-1). A panel consisting of p63, paired box gene 8 (PAX8), and INI-1 is most optimal in distinguishing UC from CDC and RMC. A subset of urothelial carcinoma of upper urinary tract may be positive with PAX8.     

Nephrogenic adenoma: an update on an innocuous but troublesome entity

Nephrogenic adenoma (NA) is a rare benign lesion of the urothelial tract that is typically preceded by some form of genitourinary insult. The pathogenesis of NA is not entirely clear. Although generally presumed to be a metaplastic process of the urothelium, recent evidence suggests that NA may in fact be derived from detached renal tubular cells implanting along the urothelial tract in previously injured areas, at least in cases associated with a kidney transplant. On light microscopy, NA shows a variety of patterns, including tubulocystic, papillary, and much less frequently solid, that often coexist. Recognition of its characteristic patterns, and awareness of its unusual architectural and cytologic features, is key to making the diagnosis of NA and distinguishing this lesion from malignant neoplasms occurring at the same sites, in particular, clear cell carcinoma, nested or microcystic variants of urothelial carcinoma and prostatic adenocarcinoma. Although straightforward in most cases, the correct diagnosis may be difficult to make on limited tissue samples. A number of immunohistochemical markers have been studied in an attempt to characterize NA; however, to date there is no specific immunohistochemical profile to distinguish this lesion from its malignant mimickers, although PAX2, a new marker, may prove to be helpful in this regard. Clinicopathologic correlation with careful attention to morphology remains the pillar in establishing the correct diagnosis.     

涎腺基底细胞腺瘤和腺癌与腺样囊性癌的比较观察

目的 研究涎腺基底细胞腺瘤和基底细胞腺癌与腺样囊性癌的形态学特征、免疫表型和鉴别诊断。方法 对5例基底细胞腺瘤，5例基底细胞腺癌和7例腺样囊性癌进行了免疫组化和双重免疫电镜(2例)的观察。结果 基底细胞腺瘤和基底细胞腺癌在免疫表型方面非常相似；基底细胞腺瘤(癌)与腺样囊性癌之间在免疫表型和超微结构方面有一定的差别。结论 基底细胞腺瘤和基底细胞腺癌的鉴别诊断基于两者的生长方式和组织学特征。免疫组化和免疫电镜观察有助于基底细胞腺瘤(癌)与腺样囊性癌的鉴别诊断。     

Colonic adenocarcinoma metastatic to the urinary tract versus primary tumors of the urinary tract with glandular differentiation: a report of 7 cases and investigation using a limited immunohistochemical panel

OBJECTIVE: To determine whether a limited immunohistochemical panel can help differentiate metastatic colonic adenocarcinoma from primary enteric-type adenocarcinoma of the urinary tract and urothelial (transitional cell) carcinoma with glandular differentiation, which appear morphologically similar but most often necessitate different treatment protocols. DESIGN: We examined lower urinary tract tumors (5 urinary bladder, 2 urethral) from 7 patients with a history of colonic adenocarcinoma. The differential diagnoses in these cases included metastatic colonic adenocarcinoma, primary enteric-type adenocarcinoma of the urinary tract, and urothelial carcinoma with glandular differentiation. An immunohistochemical panel consisting of cytokeratin 7 (CK-7), cytokeratin 20 (CK-20), and villin was evaluated in all cases. Four primary enteric-type adenocarcinomas of the urinary tract and 5 conventional urothelial carcinomas were also studied to compare morphologic features and immunohistochemical staining patterns. RESULTS: Of the 7 cases, 6 were determined to be metastatic colonic adenocarcinoma and 1 was diagnosed as a primary urothelial carcinoma with glandular differentiation. All 6 metastatic colonic adenocarcinomas, 6 of the 7 primary colonic adenocarcinomas, and all 4 primary enteric-type adenocarcinomas of the urinary tract were CK-20 positive (1 was CK-20 negative), villin positive, and CK-7 negative. The single urothelial carcinoma with glandular differentiation and all 5 control cases of urothelial carcinoma were CK-7 and CK-20 positive, and villin negative. CONCLUSIONS: We conclude that (1) villin is expressed in primary enteric-type adenocarcinoma of the urinary tract; (2) in difficult cases, urothelial carcinoma with glandular differentiation can be distinguished from colonic adenocarcinoma because the former is CK-7 positive, CK-20 positive, and villin negative, whereas the latter is CK-20 positive, villin positive, and CK-7 negative; (3) clinical information is essential when evaluating lower urinary tract tumors that are clinically and morphologically similar to enteric-type adenocarcinoma of the urinary tract; and (4) the similar immunohistochemical profiles of metastatic colonic adenocarcinoma and primary enteric-type adenocarcinoma of the urinary tract may be in keeping with the hypothesis that the latter arise from intestinal metaplasia.     

Nephrogenic adenoma of the urinary bladder: a comparison of its cytologic and histopathologic features in ten cases

We studied the cytologic features of ten cases of nephrogenic adenoma, a benign proliferative lesion of urothelium that is typically associated with prior trauma or urothelial irritation. The typical cytologic features consisted of numerous vacuolated polygonal cells, including signet-ring-like cells, that were isolated or formed papillae or loose groups. Columnar cells and occasional glandular structures were also seen. The cells typically exhibited no or only mild nuclear atypia. There was often a background of acute inflammation. The differential diagnosis of urinary cytologic specimens with these features includes degenerative changes, changes induced by instrumentation, and, most importantly, adenocarcinoma and low-grade papillary transitional-cell carcinoma.     

Malignant glandular lesions and glandular differentiation in invasive/noninvasive urothelial carcinoma of the urinary bladder

Although the lumen of the urinary bladder is covered with only urothelial epithelium, malign glandular lesions (eg, nonurachal adenocarcinoma) and benign lesions (eg, cystitis cystica and cystitis glandularis) can also rarely occur in this site due to its characteristic embryologic development. Glandular differentiation is uncommon in urothelial carcinomas and is even less common in noninvasive urothelial cancers. In addition, in situ urothelial carcinomas are more likely to progress in the presence of glandular differentiation toward high-grade urothelial carcinomas and/or aggressive urothelial carcinomas. Pure nonurachal adenocarcinomas and mixed carcinomas (urothelial carcinoma and adenocarcinoma) are very rare, and their pathogenesis is not clear. Most of the nonurachal adenocarcinomas are thought to arise on the grounds of cystitis glandularus with intestinal metaplasia. Here, I present 2 cases with noninvasive urothelial carcinoma with substantial glandular differentiation showing progression to signet ring cell carcinoma and invasive urothelial carcinoma, one case with mixed carcinoma (urothelial carcinoma and adenocarcinoma) and another case with pure adenocarcinoma developing from cystitis glandularis with intestinal metaplasia, and discuss malign glandular lesions in the bladder and invasive/noninvasive urothelial carcinomas with glandular differentiation.     

Hepatocyte nuclear factor-1β expression in clear cell adenocarcinomas of the bladder and urethra: diagnostic utility and implications for histogenesis

The histogenesis of clear cell adenocarcinoma of the bladder/urethra is uncertain. Hepatocyte nuclear factor-1β is a homeodomain protein that has been reported to be frequently overexpressed in ovarian clear cell adenocarcinoma in comparison with rare or no expression in other types of epithelial ovarian tumors. We assessed the expression of hepatocyte nuclear factor-1β in a series of 18 clear cell adenocarcinomas of the bladder and urethra and compared it with that of invasive high-grade transitional/urothelial carcinoma (n = 35); adenocarcinomas of the bladder, urethra, and paraurethral glands (n = 21); as well as nephrogenic adenomas of the bladder (n = 8). Staining intensity and extent were evaluated using a 4-tiered grading system (0-3). A case was considered positive for hepatocyte nuclear factor-1β if 10% or more of tumor cells showed at least weak nuclear staining or if any moderate or strong nuclear staining was observed. All 18 clear cell adenocarcinomas exhibited nuclear staining in at least 50% of tumor cells (16 strong, 1 moderate, and 1 weak with focal strong nuclear staining) in comparison with positive nuclear staining (moderate) in 1 of 21 bladder adenocarcinoma, 1 of 35 invasive high-grade transitional/urothelial carcinoma (weak to moderate staining), and 2 of 8 nephrogenic adenomas (1 weak and 1 moderate to strong staining). We concluded that hepatocyte nuclear factor-1β is a useful marker in differentiating clear cell adenocarcinomas of the bladder/urethra from invasive high-grade transitional/urothelial carcinoma and other types of bladder adenocarcinomas and to a lesser extent from nephrogenic adenomas. Hepatocyte nuclear factor-1β is of no diagnostic utility in discriminating primary bladder/urethral clear cell adenocarcinomas from metastatic clear cell adenocarcinomas of the female genital tract to the bladder/urethra. From a histogenesis standpoint, although the expression of hepatocyte nuclear factor-1β in both gynecologic and urologic tract clear cell adenocarcinomas may point to a Müllerian derivation/differentiation, this immunohistochemical evidence is insufficient to completely exclude an urothelial association.     

Abundant expression of AMACR in many distinct tumour types

AIMS: Alpha-methylacyl-CoA racemase (AMACR), a mitochondrial and peroxisomal enzyme, is a valuable tool to confirm the diagnosis of prostate cancer, especially if combined with basal cell markers. To extend this diagnostic utility to other neoplasias, we comprehensively surveyed AMACR expression in human tumours. METHODS: We performed immunohistochemical analyses on tissue microarrays of AMACR expression in over 125 different human tumour types and 80 normal tissues. RESULTS: Microarray analysis revealed that tumours with prominent AMACR expression included adenocarcinomas of the prostate (72%), hepatocellular carcinomas (77%), papillary renal cell carcinomas (70%), and colorectal adenocarcinomas (71%). AMACR expression was equally frequent in colorectal adenomas and carcinomas. No significant difference in AMACR expression between untreated and hormone-refractory prostate cancers was observed. In the thyroid, AMACR expression was found in 42% of the follicular carcinomas but in only 16% of follicular adenomas. However, a more detailed analysis on a thyroid tissue microarray did not confirm a significant difference of AMACR expression in follicular adenoma and carcinomas. CONCLUSION: Taken together, the results indicate that AMACR is expressed in a wide variety of adenocarcinomas, and its diagnostic utility is restricted to specific areas.     

肾源性腺瘤临床病理和免疫组化分析

目的探讨肾源性腺瘤(nephrogenic adenoma,NA)的临床病理表现和免疫组化特征。方法收集5例膀胱和输尿管NA,分析其临床病理和免疫表型特征。结果 3例NA位于膀胱,2例位于输尿管。眼观NA呈乳头状或息肉状,镜下见病变主要由增生上皮细胞形成的小管状、囊状和乳头状结构组成;增生上皮为单层立方状或扁平状,部分呈"鞋钉"样;间质慢性炎。免疫组化染色示增生上皮细胞呈PAX2、CK7、EMA、AMACR/P504S(+),p63、CD10、CD31、PSA(-),Ki-67增殖指数<2%。结论 NA是较少见的瘤样病变,可误诊为其他肿瘤(甚至腺癌)。熟悉其病理学和免疫表型特征是正确诊断的关键。     

Pyloric gland adenoma-- how to diagnose?

The term "pyloric gland adenoma" reflects its etiogenesis from deep mucoid glands in the stomach. The diagnosis can be confirmed by immunohistochemistry. Typically, pyloric gland adenomas are strongly positive for Mucin 6 (deep mucoid gastric glands). These lesions express Mucin 6 over the whole lesion up to the surface often only with a small layer of columnar epithelium expressing Apomucin 5AC. The amount of mucin 5AC which is expressed on normal within the apical foveolar epithelium might vary from case to case. Combination or transdifferentiation with ordinary tubular (intestinal differentiation) adenoma can be observed. The gastric corpus mucosa of elderly female patients with autoimmune gastritis is highly affected. The frequency of pyloric gland adenoma is given in the literature being 2.7% of all gastric polyps. Therefore pyloric gland adenomas are not that rare that one might assume. Only a few publications are available which makes one think that these lesions are frequently misinterpreted. Pyloric gland adenomas can arise in gastric heterotopia and gastric metaplasia in the whole gastrointestinal tract. The clinical significance is given by a 30% rate of malignant transformation. These cases represent for the most well differentiated early adenocarcinomas which are known to have an excellent prognosis after complete polypectomy and limitation to the mucosal layer.     

Elevated expression of caveolin-1 in adenocarcinoma of the colon

Caveolins 1, 2, and 3 are the principal proteins of caveolae, the vesicular invaginations of the plasma membrane. Several reports have suggested that caveolin-1 may have a role in cellular transformation and tumorigenesis. We studied the expression of caveolin-1 and caveolin-2 in normal epithelium, adenoma, and adenocarcinoma of the colon and their possible role in tumorigenesis. Formalin-fixed, paraffin-embedded sections of 41 cases of adenocarcinoma and 13 cases of adenoma of the colon were stained immunohistochemically with anti-caveolin-1 and anti-caveolin-2 antibodies. The expression of caveolin-1 was elevated in the overwhelming majority of the adenocarcinomas, while most normal colonic epithelium and adenomas showed little or no staining. There was significant statistical correlation of the expression of caveolin-1 with adenocarcinoma but not with tumor stage. Expression of caveolin-2 was undetectable in all of the normal colonic glands, adenomas, and carcinomas. We discuss the possible clinical implications of our findings within the context of caveolins and signal transduction.     

Primary adenocarcinoma of the renal pelvis with special reference to histochemical observations

A case of adenocarcinoma of the renal peivis is presented. The patient was an 84-year-old man suffering from longstanding right-sided nephrolithiasis. Surgical resection of the right kidney revealed adenocarcinoma with slight stromal invasion. A tubulovillous adenoma, which was morphologically similar to an adenoma of the large Intestine, was also found adjacent to the adenocarcinoma. The pelvic epithelium neighboring the lesion revealed Intestinal metaplasla. Histochemical studies revealed that the tumor In the patient and adenocarcinomas or adenomas of the large intestine have similar properties of cytoplasmic mucin. These findings suggest that the epithelium with intestinal metaplasia may have developed into the adenoma and flnally transformed into the adenocarclnoma. In addition, only tumor cells with severe atypia, most of which morphologically corresponded to adenocarcinoma, demonstrated positive nuclear staining for anti-p53. This suggests that p53 may play an important role In the malignant transformation of adenomas into adenocarcinomas, as is the case in the large intestine.     

Comprehensive analysis of HE4 expression in normal and malignant human tissues.

The HE4 (WFDC2) gene encodes a WAP-type four disulphide core domain-containing protein with a presumptive role in natural immunity. Multiple studies have consistently identified upregulation of HE4 gene expression in carcinomas of the ovary; however, the expression in normal and malignant adult tissues has not been examined in detail. Here, we examined the expression of the HE4 gene and protein in a large series of normal and malignant adult tissues by oligonucleotide microarray and tissue microarray, respectively. HE4 gene expression was highest in normal human trachea and salivary gland, and to a lesser extent, lung, prostate, pituitary gland, thyroid, and kidney. In a series of 175 human adult tumors, gene expression was highest in ovarian serous carcinomas. However, adenocarcinomas of the lung, and occasional breast, transitional cell and pancreatic carcinomas had moderate or high levels of HE4 expression. Using tissue microarrays and full tissue sections of normal and 448 neoplastic tissues, HE4 immunoreactivity was found in normal glandular epithelium of the female genital tract and breast, the epididymis and vas deferens, respiratory epithelium, distal renal tubules, colonic mucosa, and salivary glands, consistent with HE4 gene expression. In addition to consistent positivity in ovarian carcinoma, some pulmonary, endometrial, and breast adenocarcinomas, mesotheliomas, and less often, gastrointestinal, renal and transitional cell carcinomas were also positive. Knowledge of the expression patterns of HE4 in our survey is useful for application in histopathologic diagnosis, and should be taken into consideration in future studies that examine the role of HE4 as a serological tumor biomarker or as a target for gene-based therapy.